Roflumilast in Non-CF Bronchiectasis Study

• ClinicalTrials.gov Identifier: NCT03428334
• Recruitment Status: Completed
• First Posted: February 9, 2018
• Last Update Posted: October 1, 2019
• Sponsor: The University of Hong Kong
• Information provided by (Responsible Party): James Chung-Man HO, The University of Hong Kong

Tracking Information

• First Submitted Date: January 26, 2018
• First Posted Date: February 9, 2018
• Last Update Posted Date: October 1, 2019
• Actual Study Start Date: May 10, 2018
• Actual Primary Completion Date: August 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2018)

sputum leukocyte density [ Time Frame: Reduction of sputum leukocyte density in 4 weeks ]

Sputum leukocyte density is measured within 2 hours of collection by a designated technician, based on five aliquots chosen randomly from the center of a fresh specimen, which are then serially diluted with phosphate-buffered saline (PBS) and read with a light microscope and a hemocytometer

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Roflumilast in Non-CF Bronchiectasis Study
• Official Title: A 4-week Single-arm Study of Roflumilast in Stable-state Non-cystic Fibrosis Bronchiectasis

Brief Summary

This is a single-arm, open label, Phase II study of Roflumilast in stable-state non-cystic fibrosis bronchiectasis subjects.

Bronchiectasis refers to a suppurative lung condition characterized by pathological dilatation of bronchi. The predominant aetiology of bronchiectasis in the Western population is related to cystic fibrosis (CF), which is genetically determined. Bronchiectasis due to other causes are generally grouped under the term "non-CF bronchiectasis", which accounts for practically all cases that are seen commonly in Hong Kong and many other Chinese populations.

The main pathogenesis of non-CF bronchiectasis involves airway inflammation, abnormal mucus clearance and bacterial colonization, resulting in progressive airway destruction and distortion. The current treatment strategies mainly focus on targeting the key elements in the pathogenesis of non-CF bronchiectasis.

In patients with bronchiectasis, there is also neutrophilic inflammation as in COPD. It is hypothesized that roflumilast can improve airway inflammation, sputum volume and sputum inflammatory markers in patients with bronchiectasis.

This study aims to investigate the effect of short-term (4-week) treatment with roflumilast on neutrophilic airway inflammation in stable-state non-CF bronchiectasis.

Detailed Description

Apart from regular chest physiotherapy and postural drainage to help clearing mucus from bronchiectatic airways, inhalational and parenteral antibiotics have also been used to reduce the bacterial load in destroyed airways, thus controlling and preventing infective exacerbations. In recent years, accumulated evidence has suggested a central role of airway inflammation and immune dysregulation in the evolution of non-CF bronchiectasis. The classical type of airway inflammation is neutrophilic, with abundance of neutrophils in sputum, bronchoalveolar lavage fluid and bronchial biopsy from patients with non-CF bronchiectasis, even in clinically stable-state. The recruitment and trafficking of neutrophils to bronchiectatic airways are mediated via various pro-inflammatory cytokines like interleukin-1β (IL-1β), IL-8, tumour necrosis factor (TNF)-alpha and leukotriene B4 (LTB4). Investigators have also shown in an in vitro model that sputum from patients with non-CF bronchiectasis could stimulate IL-6 production from normal human bronchial epithelial cells, mediated via TNF-alpha. Recent data have suggested the involvement of Th17 immunity, in which Th17-polarized Cluster of Differentiation 4 (CD4) T cells can respond to bacteria (especially Pseudomonas aeruginosa) in bronchiectatic airways by elaboration of IL-17, leading to downstream IL-8 release from airway epithelial cells, neutrophil chemotaxis, mucus hypersecretion and formation of ectopic lymphoid follicles. This IL-17 driven pathway can further aggravate the vicious circle of key pathogenetic mechanisms in non-CF bronchiectasis. In previous studies, airway neutrophilic inflammation as indicated by sputum neutrophil count was inversely correlated with lung function (forced expiratory volume in 1 second, FEV1) and directly with duration of disease and severity (Bronchiectasis Severity Score, BSI) in stable non-CF bronchiectasis. Investigators have also demonstrated that sputum elastase, released from airway neutrophils, significantly correlated with 24-hour sputum volume, number of bronchiectatic lobes, percent predicted FEV1, and sputum leukocyte count in stable-state bronchiectasis. Patients with non-CF bronchiectasis harbouring Pseudomonas aeruginosa showed greater sputum neutrophilia and volume, with lower FEV1 and FEV1/forced vital capacity (FVC) ratio in previous studies from our group and others.

This study aims to investigate the extent of airway inflammation in non-CF bronchiectasis is indicated by sputum leukocyte density (primary outcome measure), pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, LTB4 and IL-17) and neutrophil elastase. Investigators hypothesize that 4-week treatment of roflumilast in stable-state non-CF bronchiectasis can result in: (1) reduction in sputum leukocyte density (primary hypothesis); (2) reduction in sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4; (3) reduction in sputum neutrophil elastase; (4) reduction in 24-h sputum volume; (5) no change in sputum bacterial colonization, load and microbiome.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-cystic Fibrosis Bronchiectasis

Intervention

Drug: Oral roflumilast

Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor is approved worldwide (including Hong Kong) for treatment of severe chronic obstructive pulmonary disease (COPD) with frequent exacerbations. Roflumilast has been shown to have anti-inflammatory effect in patients with COPD, with significant reduction of sputum absolute neutrophil count, IL-8 and neutrophil elastase compared with placebo treatment. Roflumilast can also improve the lung function parameters in patients with COPD and reduce the rate of moderate-to-severe exacerbations.

Other Name: Daxas

Study Arms

Experimental: Oral roflumilast

oral roflumilast 500 microgram daily for 4 weeks

Intervention: Drug: Oral roflumilast

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 8, 2018): 20
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 31, 2019
• Actual Primary Completion Date: August 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Aged 18 years or above, male or female.
2. Never-smokers or those who have smoked less than 100 cigarettes in their lifetime.
3. Confirmed diagnosis of non-CF bronchiectasis based on high-resolution computed tomography (HRCT) scan.
4. Significant sputum production (≥ 10 ml per day).
5. In stable-state bronchiectasis with no change in regular medications (e.g. inhaled steroid, macrolide) or exacerbations in the past 3 months.
6. Written informed consent obtained.

Exclusion Criteria:

1. Eversmokers (≥ 100 cigarettes in their lifetime).
2. Known chronic obstructive pulmonary disease or asthma.
3. Moderate to severe liver impairment (Child-Pugh B or C).
4. Known psychiatric illness with increased suicidal risks.
5. Body-mass index below 20 kg/m2.
6. Concomitant use of strong cytochrome P450 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin).
7. Patients who are hypersensitive to roflumilast or its constituents.
8. Pregnant or lactating women.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Hong Kong

Administrative Information

• NCT Number: NCT03428334
• Other Study ID Numbers: ROF2017_v1
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: James Chung-Man HO, The University of Hong Kong
• Original Responsible Party: Same as current
• Current Study Sponsor: The University of Hong Kong
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: James CM Ho, MD; The University of Hong Kong

• PRS Account: The University of Hong Kong
• Verification Date: September 2019